Which GLP-1 Is Best for Cardiovascular Benefit?

The short version: three GLP-1 medicines have heart outcome trials, but they tested different people against different comparators, so none can be crowned best.

The honest answer is that no single GLP-1 has been shown to be best for the heart. Semaglutide has the broadest set of outcome trials, including the only one in people with obesity and heart disease but no diabetes. Liraglutide and tirzepatide each have a large outcome trial in type 2 diabetes. These trials enrolled different people, used different comparators and were all funded by the manufacturer, so their results cannot be ranked against one another.^1,2

This guide lays out what each major cardiovascular outcome trial tested, what it found, and what each FDA label currently says about heart protection. It is general information, not advice about which medicine suits a particular person.

What do the cardiovascular outcome trials show?

A cardiovascular outcome trial follows people for years and counts hard events: death from cardiovascular causes, heart attack and stroke. The combination of those three is often called MACE. Four trials matter most for this question.

Read the last column with the comparator in mind. In SELECT, SUSTAIN-6 and LEADER the comparison was against placebo, so the results show what the drug added on top of usual care. In SURPASS-CVOT the comparison was against another GLP-1 medicine that had already been shown to lower cardiovascular events, which is a harder test and answers a different question.²

Semaglutide: the SELECT and SUSTAIN-6 trials

SELECT is the trial most relevant to people who are using a GLP-1 for weight. It enrolled adults aged 45 or older with established cardiovascular disease and a body-mass index of 27 or higher, and it excluded anyone with diabetes. Participants took semaglutide 2.4 mg weekly or placebo for a mean follow-up of about 40 months. A primary event occurred in 569 of 8,803 people (6.5%) on semaglutide and 701 of 8,801 (8.0%) on placebo.¹

The trial also recorded a cost. Adverse events led to permanent discontinuation of the study drug in 16.6% of the semaglutide group, about double the 8.2% in the placebo group.¹ Anyone reading the headline hazard ratio should read that number beside it.

SUSTAIN-6 was a smaller, earlier trial in type 2 diabetes. It was designed to show that semaglutide was not worse than placebo for heart safety, and it went further: MACE occurred in 6.6% on semaglutide and 8.9% on placebo. Nonfatal stroke was lower (hazard ratio 0.61, 95% confidence interval 0.38 to 0.99), while nonfatal heart attack and cardiovascular death did not differ significantly. The same trial found more retinopathy complications with semaglutide (hazard ratio 1.76, 1.11 to 2.78).⁸

Liraglutide: the LEADER trial

Liraglutide was the first GLP-1 to show a cardiovascular benefit in a large trial. Over a median 3.8 years, MACE occurred in 13.0% of the liraglutide group and 14.9% of the placebo group. Deaths from cardiovascular causes were also lower (4.7% vs 6.0%), as were deaths from any cause (8.2% vs 9.6%), although the authors noted that no adjustment for multiple comparisons was made for the secondary outcomes.³ Liraglutide is a daily injection, and the trial was done in people with diabetes, so it does not speak to weight-loss use in people without diabetes.

Tirzepatide: the SURPASS-CVOT trial

Tirzepatide acts on two receptors, GIP and GLP-1. Its main outcome trial, SURPASS-CVOT, compared it with dulaglutide in 13,299 randomized adults who had type 2 diabetes and atherosclerotic cardiovascular disease. MACE occurred in 801 of 6,586 people (12.2%) on tirzepatide and 862 of 6,579 (13.1%) on dulaglutide. The hazard ratio was 0.92 with a 95.3% confidence interval of 0.83 to 1.01. That met the prespecified test for noninferiority, but not the test for superiority (P = 0.09). More gastrointestinal adverse events occurred in the tirzepatide group.²

A later analysis of the same trial looked at people with and without a history of heart failure. Among those with heart failure, the hazard ratio for all-cause death or heart-failure hospitalization or urgent visit was 0.83 (0.70 to 0.99); without heart failure it was 0.88 (0.78 to 1.00). That analysis was written with Eli Lilly employees as authors, and subgroup findings carry less weight than the main result.⁹

The practical reading of SURPASS-CVOT is that tirzepatide is at least as good as dulaglutide for heart events in this population. It is not evidence that tirzepatide beats semaglutide, because semaglutide was not in the trial.

What do the FDA labels say?

Trial results become labeled uses only when the FDA agrees the evidence supports them. The current labels differ in a way that matters for this question.

So a cardiovascular label exists for semaglutide in both diabetes and obesity, and for tirzepatide in diabetes. For people using tirzepatide for weight alone, the Zepbound label does not carry a heart-event indication, and a dedicated outcome trial in people with obesity but no diabetes is not part of the evidence described here.⁷

Is the benefit from weight loss or from the drug itself?

The trials cannot fully separate the two. These medicines lower weight, blood sugar and blood pressure, and each of those can reduce cardiovascular risk. The outcome trials above were not designed to separate those routes, so any statement about mechanism is a hypothesis rather than a finding. What the trials do show is that, in the populations studied, taking the medicine alongside usual care was followed by fewer events than placebo or the comparator.

Who was in these trials, and who was not?

Every trial above enrolled people who already had cardiovascular disease, or in LEADER and SUSTAIN-6 were at high risk of it. SELECT required established disease. SURPASS-CVOT enrolled people whose average age was 64 and of whom 29% were women.² None of these trials tested whether starting a GLP-1 prevents a first heart attack in a healthy person with obesity, so the findings should not be stretched to cover that case. The same holds for compounded products: the trials used the manufacturers' FDA-approved products, and compounded versions are not FDA-approved.¹⁰

How to use this when talking with a clinician

Questions that follow from the evidence are more useful than asking which drug is best. Does the person have established heart disease, diabetes, both or neither? Does the label for the product being considered include a cardiovascular indication for that situation? Which side effects, especially gastrointestinal ones and, in diabetes, eye changes, are a concern? A clinician can weigh these with the person's own history. For related reading, see how tirzepatide and semaglutide compare on weight loss and labeling, what GLP-1 side effects look like in trials, and what is known about muscle loss on GLP-1 medicines.

Quick questions

Which GLP-1 is best for heart health?

No trial has shown one GLP-1 to be best. Semaglutide, liraglutide and tirzepatide each lowered cardiovascular events in their own trials, in different populations and against different comparators.{SELECT,LEADER,SURPCVOT}

Does Wegovy lower the risk of heart attack and stroke?

In SELECT, adults with heart disease and overweight or obesity but no diabetes had fewer heart attacks, strokes and cardiovascular deaths on semaglutide 2.4 mg than on placebo (6.5% vs 8.0%). The Wegovy label includes this indication for adults with established cardiovascular disease.{SELECT,DMWEGT}

Does tirzepatide protect the heart?

In SURPASS-CVOT, tirzepatide was noninferior to dulaglutide for cardiovascular events in adults with type 2 diabetes and heart disease, without showing superiority. Mounjaro's label includes a cardiovascular indication for type 2 diabetes; Zepbound's does not.{SURPCVOT,DMMOUNJ,ZEPB}

Do GLP-1 medicines help people without diabetes?

SELECT enrolled people without diabetes who had heart disease and overweight or obesity, and found fewer cardiovascular events with semaglutide. It did not test people without existing heart disease.{SELECT}

Are compounded GLP-1s covered by these results?

No. The trials tested the manufacturers' FDA-approved products. Compounded versions are not FDA-approved.{FDAGLP}

More briefs

• Tirzepatide vs Semaglutide: What the Trials Show
• Compounded Tirzepatide vs Zepbound: What Actually Differs
• Is There an Oral GLP-1?
• Does a GLP-1 Cause Muscle Loss?